Unpredicted aversive stimuli trigger rapid emotional and behavioral reactions, and if persistent, may contribute to the emergence of depressive-like symptoms in both animals and humans (Knoll and Carlezon, 2010). The lateral habenula (LHb) processes aversive stimuli and disappointment and drives aversive behaviors (Matsumoto and Hikosaka, 2007; Stamatakis and Stuber, 2012). The LHb has been implicated in addiction (Lecca, S. et al. 2014).
Aversive stimuli, and more generally stressors, increase the activity of LHb neurons projecting to monoaminergic centers including the ventral tegmental area and the raphe nucleus (Hikosaka, 2010; Matsumoto and Hikosaka, 2007; Proulx et al., 2014). Indeed in mice exposed to foot-shocks, the EPSC paired pulse ratio obtained by optogenetic driven activation of LHb terminals onto midbrain GABA neurons is rapidly decreased indicating a higher glutamate release from LHb axons to midbrain neuronal populations (Stamatakis and Stuber, 2012). The repetitive exposure to aversive environmental stimuli produces instead an aberrant and persistent hyperactivity of LHb neurons, which has been proven instrumental for the emerging of depressive symptoms (Li et al., 2011; Li et al., 2013) (Meye, Valentinova, Lecca et al., 2015).
The underlying mechanisms implicate distinct mechanisms; firstly a CaMKIIβ- and GluA1-dependent strengthening of AMPA-mediated transmission (Li et al., 2013) (Meye, Valentinova, Lecca et al., 2015); and secondly a reduction in the GABA component of GABA-Glutamate co-release typical of the entopeduncular nucleus-to-LHb synapse (Proulx et al., 2014; Shabel et al., 2014). Altogether, these findings indicate that the induction and maintenance of depressive behaviors may require complex and temporally distinct synaptic modifications relying on specific inputs and outputs of LHb neurons (Lecca et al., 2014).
Neuronal excitability throughout the central nervous system relies, at least in part, on the slow GABA-dependent inhibition mediated by GABAB receptors (GABABRs) and G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels (Luscher et al., 1997). Repeated stressful events lead to the dysregulation of GIRK-dependent signaling (Lemos et al., 2012a; Lemos at al., 2012b). Furthermore, analysis of GIRK gene expression and function in rodents (Cornelisse et al., 2007; Lujan et al., 2014), and polymoprhisms in the GIRK gene in human cohorts provide strong arguments for GABAB-GIRK implications in the development of depressive symptoms (Bagdy et al., 2012).